Bortezomib (BTZ) is an anti-neoplastic agent for intravenous injection (IV) or subcutaneous (SC) use. The structure of bortezomib is:

Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis which can affect multiple signalling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumour growth in vivo in nonclinical tumour models, including multiple myeloma.
Data from in vitro, ex-vivo, and animal models with bortezomib suggest that it increases osteoblast differentiation and activity and inhibits osteoclast function. These effects have been observed in patients with multiple myeloma affected by an advanced osteolytic disease and treated with bortezomib.
Delanzomib (DLZ), ([(1R)-1-[[(2S,3R)-3-Hydroxy-2-[[(6-phenylpyridin-2-yl)carbonyl]amino]-1-oxobutyl]amino]-3-methylbutyl]boronic acid), is an anti-neoplastic agent for intravenous injection (IV), oral or subcutaneous (SC) use. The structure of delanzomib is:

Delanzomib is also a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. Experiments have demonstrated that delanzomib is cytotoxic to multiple myeloma cell lines in vitro (Piva et al. Blood 2008; 111:2765-75, Dorsey et al., J. Med Chem 2008; 51:1068-72). Delanzomib causes a reduction in tumour growth in vivo in nonclinical tumour models, including multiple myeloma (Sanchez et al., Br. J. Haematol 2010; 148:569-81).
Ixazomib (IXZ) is an anti-neoplastic agent for intravenous injection (IV), oral or subcutaneous use. Ixazomib is formulated with citric acid for clinical use: the citrate hydrolyses immediately on contact with plasma or aqueous solutions (Kupperman et al., Cancer Res. 2010; 70:1970-80). The final formulation is termed ixazomib citrate, originally designated ‘MLN9708’, which contains the active drug component ‘MLN2238’ (ixazomib) and a citric acid moiety.
The structure of Ixazomib (MLN2238) ([(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methyl-butyl]boronic acid) is provided below:

The structure of Ixazomib citrate (MLN9708) (2,2′-{2-[(1R)-1-{[N-(2,5-Dichlorobenzoyl)glycyl]amino}-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid) is provided below:

Ixazomib is also a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells.
Kupperman and co-workers (Kupperman et al., Cancer Res. 2010; 70:1970-80) describe the physiochemical, phamocokinetic, pharmacodynamic, antitumoral activity and interactions of ixazomib with the proteasome compared with bortezomib. Both bortezomib and ixazomib bind preferentially to the β5 site of the 20S proteasome, also binding to the β2 and β1 sites at higher concentrations. Although the affinity for the active sites in the proteasome is approximately equal for ixazomib and bortezomib, ixazomib was found to remain bound to the proteasome for a shorter time period. The proteasome dissociation half-life of ixazomib is approximately 18 minutes, whereas the dissociation half-life of bortezomib is approximately 110 minutes, i.e. ixazomib is released approximately 6-fold faster than bortezomib. Ixazomib is cytotoxic to a variety of cancer cell lines in vitro including melanoma, lung cancer and colorectal cancer cell lines. Ixazomib also exhibited antitumoral activity in vivo in several preclinical models. In CWR22 human prostate cancer xenografts, both bortezomib and ixazomib showed effective anti-tumoral activity at their maximum tolerated dose (MTD). Ixazomib proved more effective than bortezomib at half the MTD. In WSU-DLCL2 lymphoma xenograft model, ixazomib showed significant anti-tumoral activity whereas bortezomib was ineffective at its MTD. Similarly, in Oci-Ly7-Luc model, representing disseminated lymphoma, animals treated with ixazomib exhibited an improved antitumoral effect compared with bortezomib. Ixazomib was also found to have oral bioavailability, meaning that oral dosing may be an option for treatments including ixazomib (Kupperman et al., Cancer Res. 2010; 70:1970-80). Lee and co-workers extended this analysis to include several further lymphoma models, both xenograft based lymphoma models (OCI-Ly10 and PHTX22L), and genetically-engineered mouse model iMyccα/Bcl-XL, designed to be more representative of the clinical progression of human cancers. In each case, MTD level treatment with ixazomib was as least as effective as MTD-level treatment with bortezomib. In the case of PHTX22L xenografts only ixazomib was found to exhibit an anti-tumoral effect. Ixazomib was also effective in the alleviation of osteolytic bone disease in the DP54-Luc model (Lee et al., Clin. Cancer Res. 2011; 17:7313-23). It should be noted that, due to the higher MTD exhibited by ixazomib in the animal models, ixazomib was delivered at more than tenfold higher concentrations than bortezomib in the studies of Kupperman and Lee et al., therefore the improvements seen may be related to the higher doses delivered rather than the chemical properties of ixazomib. Nevertheless, reduced toxicity compared with bortezomib is an important feature of ixazomib, defining its potential clinical applicability (meaning that increased doses of ixazomib compared with bortezomib are clinically feasible).
When assessed in clinical trials, ixazomib citrate has been found to be well tolerated by both oral and intravenous routes, with MTD values which are generally greater than those exhibited by bortezomib. Ixazomib citrate has been trialled for the intravenous treatment of various solid tumours and non-Hodgkins lymphoma as well as oral treatment of multiple myeloma (reviewed in Allegra et al., Leukemia Research 2014; 38: 1-9). Phase III clinical trails are planned for evaluation of ixazomib citrate in combination with Revlimid® (lenalidomide) and dexamethasone for treatment of myeloma or systemic light chain amyloidosis, delivered orally in each case (clintrials.gov identifiers NCT01564537, NCT01659658, NCT01850524 and NCT0218141).
Carfilzomib (CFZ) has the structure:

Carfilzomib causes stronger inhibition of the chymotrypsin-like activity of the proteasome in blood of patients than bortezomib—88% at the highest dose used in the phase I trial, where the maximal tolerated dose has not been reached (O'Conner et al, 2009 Clin. Cancer Res. 15, 7085-7091). In phase II trials, carfilzomib has achieved 24% partial response rate in a heavily pretreated patient population, a median of five prior lines of multidrug therapy (Kisselev et al, Chemistry & Biology 19, 27 Jan. 2012, 99-115). Incidents of peripheral neuropathies are greatly reduced compared to bortezomib (Molineaux, S. M. (2012), Clin. Cancer Res. 18, 15-20).
Oprozomib (OPZ) has the structure:
Oprozomib is an orally available analogue of carfilzomib (Zhou, H. J., et al. (2009). J. Med. Chem. 52, 3028-3038).
MG-132 has the structure:
MG-132 is a rapidly reversible, potent inhibitor that blocks proteasomes by forming a hemiacetal with the hydroxyl of the active site threonines (Kisselev et al, Chemistry & Biology 19, 27 Jan. 2012, 99-115).
Marizomib has the structure:
Marizomib is derived from a marine microorganism, Salinispora tropica (Chauhan et al, Cancer Cell 8, 407-419). Marizomib inactivates proteasomes by esterifying the catalytic threonine hydroxyl. The opening of the β-lactone ring is followed by formation of a tetrahydrofuran ring as the result of nucleophilic displacement of the chloride atom of the inhibitor (Groll et al, J. Am. Chem. Soc. 128, 5136-5141). All β-lactone adducts are slowly hydrolyzed by water, resulting in reactivation of the proteasome (Dick et al, J. Biol. Chem. 272, 182-188). Marizomib is the most potent of all proteasome inhibitors presently undergoing clinical trials. It produces stronger (up to 100%) and longer-lasting inhibition of the chymotrypsin-like sites and also targets the trypsin-like and the caspase-like sites (Potts et al, Curr. Cancer Drug Targets 11, 254-284).
Peptides containing an exposed RGD (arginine-glycine-aspartic acid) amino acid sequence are known to bind to integrins and have been heavily studied for targeted drug delivery (for review see Temming et al Drug Resistance Updates 8 (2005) 381-402). RGD-containing peptides have also been directly trialled as anti-cancer agents, on account of their binding to alphaV beta3 integrins which are over-expressed on certain cancers and in particular on tumour vasculator. One such example is Cilengitide or EMD121974, a 5 amino acid circularised peptide containing the RGD sequence which has been tested in clinical trials for melanoma, glioblastoma and prostate cancer. Although the three amino acid RGD motif is itself immutable, the specificity and avidity of targeting can be altered by changing the number and composition of the flanking amino acid sequences. Maintaining the core RGD sequence within a circularised structure containing a D-amino acid exhibits increased stability and binding avidity for alpha integrins.
Cilengitide has been the subject of at least 38 clinical trials (14 phase I, 5 phase I/II, 17 phase II and 2 phase III) in the US and Europe in which the drug has been trialled in patients with non-small cell lung cancer, gliomas, glioblastoma, brain tumours, breast tumours, metastatic squamous cell carcinoma of the head and neck, prostate cancer, leukemia, melanoma, lymphoma and advanced solid tumours, Kaposi's sarcoma. In terms of combination therapies, cilengitide has been tested in combination with Bevacizumab, Procarbazine, Radiochemotherapy (standard radiotherapy and cisplatin and vinorelbine based chemotherapy), Temozolomide, Corticosteriods, Radiation Therapy, Cediranib maleate, Paclitaxel, Cetuximab, 5-fluorouracil (5-FU), Sunitinib malate, Venorelbine and Gemcitabine. However, none of these combinations has yet been approved by the US or European agencies.
We have found that a combination of a proteasome inhibitor with a cyclic peptide that comprises an exposed Arg-Gly-Asp (RGD) moiety yields a synergistic therapeutic effect relative to the sum of each of the individual components.